Project Summary/Abstract Migraine is a complex and debilitating neurological disorder involving the neuropeptide calcitonin gene- related peptide (CGRP). The overall objective of this project is to identify mechanisms by which peripheral CGRP causes photophobia, a painful response to non-noxious levels of light experienced by ~90% of migraine patients. Peripheral injection of CGRP causes light aversion, a response analogous to photophobia. This response in wild-type requires bright light, while in transgenic mice with globally increased CGRP receptors there is an enhanced response seen even in dim light. Interestingly, this enhanced light aversive phenotype is not seen in transgenic mice that have elevated nervous system expression of the receptor. This evidence suggests that peripheral CGRP administration may cause light aversion and activate neural pathways in an indirect mechanism. Since CGRP is one of the most potent vasodilators in the body, we hypothesize that CGRP can cause light aversion by a vascular mechanism. This hypothesis is based on findings that 1) intravenous administration of CGRP in human subjects can cause migraine pain, and 2) perivascular CGRP can sensitize the trigeminal nerve, which could alter synaptic transmission to the central nervous system. Thus, there is a mechanism by which CGRP in the periphery can sensitize the trigeminal nerve and alter sensory perception, leading to photophobia. A single aim is proposed that will establish the contribution of the vasculature in light aversive behavior. Complementary pharmacological and genetic strategies will be used. The pharmacological approach will be to co-administer a vasoconstrictor to minimize CGRP-induced vasodilation. The genetic approach will be to generate transgenic mice with conditional overexpression of CGRP receptors on endothelial and smooth muscle cells of the vasculature. This aim will provide insight into the mechanisms by which peripheral CGRP can trigger a migraine-like symptom in a preclinical mouse model of migraine.